Production of lysine and intermediates



2,839,574 Patented June 17, 1 958 ice PRODUCTION OF LYSINE AND INTERMEDIATES Marcel Servigne,'5ceaux, and Etienne Szarvasi, Cli'chy, France, assignors to lAir Liquide, Societe Anonyme pour lEtude et lExploitation des Procedes Georges Claude, Paris, France No Drawing. Application October 1, 1954 Serial No. 459,836

Claims priority, application France October 2, 1953 2 Claims. (Cl. 260-518) The object of the present invention, is a process for the synthesis of dl-lysine or, more exactly N-OL-bfiIlZGf/i-dllysine easily convertible into dl-lysine dihydrochloride, which may be used to various purposes. In particular, dl-lysine constitutes, with trytophane, one of the fundamental amino-acids utilized in biological processes for the formation of proteides. They are elements of growth of higher organisms. They constitute, nowadays, the basis for a balanced feeding of cattle.

Among the methods for the synthesis of dl-lysine proposed heretofore, only the process described in S. Patout No. 2,498,369 of February 2i, 1950 to Scott ct al., and the Eck and Marvel synthesis and its modification by Galat are sufficiently simple to be utilized industrially.

These authors use, as a starting material, cycl'ohexanone 1) which is transformed into the corresponding oxime (2) then into caprolactame (3), which, hydrolyzed and benzoylated is transformed into the e-bCIlZOYlaminocaproic acid (4). Then this product is treated with bromine and u-bromo-e-benzoylaminocaproic acid (5) is obtained, which becomes transformed, after ammonolysis, into N-e-benzoyllysine (6) from which, by hydrolysis, lysine dihydrochloride is obtained (7).

The diagram of this synthesis is as follows:

The synthesis method which is an object of the present invention has the advantage of being simpler to put in application than the above Eek and Marvel synthesis and of giving rise, in two of the intermediate operations which constitute the phases thereof to the production of two new industrial products.

This new synthesis method leads to the production of N-oc-bCllZOYl-dl-lYslIle from which, by hydrolysis, in the known manner, dl-lysine dihydrochloride is obtained.

It consists in starting from a dihalogeno-L4-butano (the halogen in this substance being designated hereinafter by X), in condensing it with sodium diethyl acctamidomalonate for transforn'iing it into a-X-butyl-diethylacetarnidomalonate, in decarboxylating this substance by means of hydrochloric acid, in benzoylating it without separating the intermediate s-amino-e-X-caproic acid hydrochloride formed, for transforming it into a-benzoyl- 21I1'liI10-e-X-C3Pl0l0 acid and finally'in subjecting this acid to ammonolysis for obtaining N-a-benzoyl-dl lysine.

One advantage of this synthesis method over the Eek and Marvel method, lies in the fact that there are introduced into the molecule, from the very first operation, the essential functions (the acid as an ester, the amine function under an acetylated form, and an halogen), while the above authors, having in the combination (4) only the acid function and one of the amine functions (under a benzoylated form), are compelled to insert an additional operation (introduction of the halogen, combination 5), before reaching the benxoyllysine. In the synthesis according to the invention, N-a-benzoyl-dl-lysine is obtained, the isomer of N-e-benzoyl-dl-lysine obtained by Eck and Marvel.

In a preferred mode of carrying out the method of the invention, the dihalogeno-L4-butane used at the start, is bromo-l-chloro-4-butane which is obtained easily from tetrahydrofuran, for instance, which is a commercial product prepared from acetylene or furfural.

With this compound used as a starting product, the first operation of the above defined method leads to the formation of O O2Ca l C O OH (III) (III) C O OH NH2(CH2)4CNHOO Calls COOH The substances II and III constitute-new industrial products, covered as such by the invention and they are capable of'various uses. First of all, considered as intermediate products in the synthesis of dl-lysine according to the invention, they make it possible to segregate the operational procedures involved in said synthesis, and to carry them out separately, at'will, in time and in space. It is thus possible toprepare. and store these compounds which constitute not only materials which can be used for the synthesis of dl-lysine, to which they impart a valuable flexibility as regards its industrial carrying out, but also raw materials capable of being, used in other chemical processes. in particular, compound libschl'orobutyldiethylacetamidomalonate) can be used as an intermediate product for the synthesis of animated acids, polypeptids or polyamids (synthetic fibres). Compound HI (-a-benzoylamino-e-chlorocaproic acid) may be used for preparing nitrogen-substituted aminated acids which assent/4 are obtained by replacing ammonia by a primary or seeondary amine such as methylamine or dimethylamine. The halogen in compound III may undergo condensations which are characteristic of the halogen group and allow the introduction of various groups into the molecule for obtaining chains of various lengths according to the nature of the substituent. The products thus obtained can be used as intermediate products in the manufacture of various chemical products.

N-u-benzoyl-dl-lysine which is obtained by means of the synthesis according to the invention, was obtained heretofore only in a roundabout manner, and chiefly from N-Ndibenzoyllysine by hydrolysis. The N-OC-bflz oyl-dl-lysine obtained by the process according to the invention is in the form of a hydrate (with one molecule of water).

The starting material, bromo-1-chloro-4-butane (1) may be prepared according to the method of Starr and Hixon (J. Amer. Chem. Soc. 1934, p. 1595) which consists in reacting PBr with B-chlorobutanol. The high cost of phosphorus tribromide used is a drawback in industrial operation and the invention covers, in itself, a new and more economical process for the preparation of bromo-l-chloro-4-butane. This process consists in reacting dry gaseous hydrobromic acid with boiling 6- chlorobutanol in the presence of a material giving an azeotrope with the water formed during the reaction.

The yield is 70% and the final product obtained is not quite pure but it is suitable for most uses.

A few examples of operational procedures characteristic of the invention will now be described.

Example I This example concerns the preparation of hromo-lchloro-4-butane.

One places, in a round 3 tube flask, provided with a device allowing the tapping ofl of the water formed and a reflux type cooler:

82.5 grams of distillated a-ehlorobutanol, B. P. =74-5 C. and 100 cm. of dry benzene.

The apparatus is connected with a HBr generator.

Hydrobromic acid is passed through the product, first at ordinary temperature, then the temperature is gradually raised until the benzene boils. The water formed during the reaction is constantly decanted off When no more water is formed, the introduction of HBr is cut ofi and benzene is distilled under a vacuum. 2 cm. of diethanolamine are added to the product and distillation is carried out under vacuum. One obtains:

Example II This example concerns the'preparation of B-chlorobutyldiethylacetamidomalonate.

One dissolves:

4.6 g. sodium in 200 'cm. absolute alcohol.

The alcohol is removed, under a vacuum, on a water bath, and 150 cm. of dry ethyl carbonate are added.

4. One adds, while stirring thoroughly:

45.5 g. of ethyl acetamidomalonate, then 35 g. of fi-chlorobromobutane and reflux heating is continued while stirring, for about 20 hours. When the reaction has been completed, the product is poured into an excess of water, the organic layer is decanted and the substance is extracted with ether. The ether is driven off, and the fi-chlorobromobutane which did not react (2 g.) together with the ethyl carbonate are driven off by means of Water vapour. The product is poured into a small cup cooled by ice and crystallization is facilitated by stirring with a glass rod. The crystals are dried after remaining a few hours in the refrigerator. After air drying, 52 to 54.5 g. of clear crystals are obtained. Melting point: 44 to 48 C. Y ield=88- 92%.

After crystallization in 95 C. alcohol, 42 to 43 g. of white crystals are obtained, melting point: 53 C. (heating stage microscope). Yield=71-72.5%. Using highly pure starting materials, one obtains raw 6-chlorobutyldiethylacetamidomalonate melting at C. (heating stage microscope) which is used as obtained.

C, percent:

Calculated=50.73 Found=50.76; 50.91

H, percent:

Calculated=7.14 Found- 7.10; 7.11

N, percent:

Calculated=4.54 Found=4.71; 4.81

These crystals are soluble in most organic solvents and insoluble in water.

Example 111 Preparation of ol-benzoylamino-e-chlorocaprolic acid. M. W.-=269.7l-C H O NCL Reflux heating is applied for a time between 4 and 20 hours on:

41 g. of 6-chlorobutyldiethylacetamidomalonate dis solved in: 350 cm. of pure HCl (d.=1.19).

The solution is evaporated to dryness on a water bath and under a vacuum. The residue is re-dissolved in 400 cm. of water and the aqueous solution is washed with twice 100 cm. of ether. The aqueous solution is transferred to a 3-tube round flask provided with a mechanical stirrer, a dropping funnel and a thermometer.

The solution is neutralized by a lye of concentrated sodium hydroxide, keeping the temperature below 10 C. Then one adds, through the dropping funnel:

10.7 g. NaOHin pellets, dissolved in an equal volume of water, then 18.5 g. of benzoyl chloride.

During the entire reaction, the temperature of the mix ture is kept below 10 C. Stirring is continued at that temperature for an hour, then the liquid is filtered and Melting point=139-140 C.

Acid number:

Calculated=207 Found=209 N, percent:

Calculated=5.l9 Found=5.11; 5.27

The product is scarcely soluble in ether, soluble in alcohol, more soluble when hot, highly soluble in acetone, insoluble in petroleum ether and inwater. The raw product may be utilized with advantage.

Example IV Preparation of N-a-benzoyl-dl-lysine monohydrate, M. C13H1803N2, H20- One heats, in a pressure bottle, during two days and a half at a temperature of 52-55 C.,

16 g. of a-benzoylamino-e-chlorocaproic acid with 350 cm? pure 34% ammonia.

One obtains:

11 g. of white crystals=melting point=215 C. (heating stage microscope).

After concentration of the mother liquor one obtains: a second product=1 g. Melting point=190-5 C. (heating stage microscope) and a third product=0.5 g. Melting point=18590 C. (heating stage microscope). Total yield=12.6 g.=85% (theoretical yield 14.5 g.).

N, percent:

Calculated: 10.44 Found=10.33; 1032 Solubility in water:

Cold, 0.4 g. per litre Boiling, 10 g. per litre.

The product is insoluble in benzene,,chloroform and acetone. It can be transformed into lysine dihydrochloride, using the Eck and Marvel method, or into dl-lysine monohydrochloride with a small modification of this method, as follows: after chlorhydric hydrolysis of the benzoyllysine, the solution is evaporated to dryness and the brown dihydrochloride obtained is treated with boiling ethanol. The insoluble fraction is separate and the filtrate is treated with pyridine for obtaining the dl-lysine monohydrochloride.

What we claim is:

l. A method for the synthesis of N-a-benzoyl-dl-lysine, consisting in starting from bromo-l-chloro-4-butane, in condensing it with sodium diethyl-acetamidomalonate for transforming it into 6-chloro-butyl-diethylacetamidomalona'ie, in decarboxylating this substance with a nonoxidizing mineral acid, in benzoylating in situ the intermediate a-amine-E-chlorocaproic acid salt formed, for transforming it into a-benzoylamino-e-chlorocaproic acid and finally in subjecting this acid to ammonolysis for obtaining N-a-benzoyl-dl-lysine.

2. A method for the synthesis of N-u-benzoyl-dl-lysine according to claim 1, wherein the bromo-1-chloro-4-butane is prepared by reacting the gaseous and dry hydrobromic acid with fi-chlorobutanol in the presence of a substance giving an azeotrope with the water formed during the reaction.

References Cited in the file of this patent UNITED STATES PATENTS 2,498,300 Scott et al. Feb. 21, 1950 2,519,038 Galat Aug. 15, 1950 FOREIGN PATENTS 618,591 Great Britain .d Feb. 24, 1949 

1. A METHOD FOR THE SYNTHESIS OF N-A-BENZOYL-DI-LYSINE, CONSISTING IN STARTING FROM BROMO-1-CHLORO-4-BUTANE, IN CONDENSING IT WITH SODIUM DIETHYL-ACETAMIDOMALONATE FOR TRANSFORMING IT INTO B-CHLORO-BUTYL-DIETHYLACETAMIDOMALONATE, IN DECARBOXYLATING THIS SUBSTANCE WITH A NONOXIDIZING MINERAL ACID, IN BENZOYLATING IN SITU THE INTERMEDIATE A-AMINO-E-CHLOROCAPROIC ACID SALT FORMED, FOR TRANSFORMING IT INTO A-BENZOYLAMINO-E-CHLOROCAPROIC ACID AND FINALLY IN SUBJECTING THIS ACID TO AMMONOLYSIS FOR OBTAINING N-A-BENZOYL-DI-LYSINE. 